MedChemComm p. 1484 - 1493 (2015)
Update date:2022-08-11
Topics:
Guan, Qi
Feng, Dongjie
Bai, Zhaoshi
Cui, Yuanhang
Zuo, Daiying
Zhai, Min'An
Jiang, Xuewei
Zhou, Wenbo
Bao, Kai
Wu, Yingliang
Zhang, Weige
A series of (3/5-aryl-1,2,4-oxadiazole-5/3-yl)(3,4,5-trimethoxyphenyl)methanone oxime derivatives were synthesized via a rapid and facile microwave-assisted synthesis method of building a 1,2,4-oxadiazole skeleton using mandelic acid as the starting material. Twenty-four target compounds were evaluated for their in vitro antiproliferative activities against three human cancer cell lines (SGC-7901, A549 and HT-1080). Among them, 16b exhibited the highest potency against different tumour cell lines, especially the A549 cell line (IC50 = 87 nM). Structure-activity relationship (SAR) studies revealed that the aryl substituent at the C-5 position on the 1,2,4-oxadiazole ring is superior to that at the C-3 position. An oxime as a connector can obviously increase the potency, contrary to that in SMART derivatives. Moreover, 16b significantly induced a cell cycle arrest in the G2/M phase and caused microtubule destabilization. Molecular docking studies provided a theoretical binding mode of 16b at the colchicine site in the tubulin dimer. Our work laid the foundation for further structure-guided design of novel tubulin polymerization inhibitors.
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